Flavonoids for Allergic Diseases: Present Evidence and Future Perspective.
Current Pharmaceutical Design, 2014, 20, 879-885.
Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
The prevalence of allergic diseases has increased worldwide during the past two decades. Change of dietary habit is thought to be one of the environmental factors, which have caused such an increase and worsened allergic symptoms, which suggests that an appropriate dietary habit may substantially prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, which are polyphenolic plant secondary metabolites ubiquitously present in vegetables, fruits and beverages, possess antioxidant and anti-allergic activities as well as immune-modulating traits. Flavonoids inhibit the activation of mast cells and basophils and therefore suppress the release of chemical mediators, synthesis of Th2 type cytokines such as interleukin (IL)-4 and IL-13, and CD40 ligand expression, They also reportedly inhibit IL-4-induced signal transduction and affect the differentiation process of naïve CD4+ T cells into effector T cell subsets. A cohort epidemiological study in Finland found a significantly low incidence of asthma in a population with a high intake of flavonoids. Moreover, various studies of flavonoids in allergic models such as asthma, atopic dermatitis, anaphylaxis and food allergy demonstrated their beneficial effects, while experience in humans is at the moment limited to respiratory allergy. Although further validation is required, it is anticipated that an appropriate intake of flavonoids may play a role in the prevention and eventually in the management of allergic diseases.
A great deal of attention is being paid to dietary habits as one of the environmental factors which increase the prevalence of allergic diseases and/or worsen allergic symptoms (1). Devereux et al pointed out that reduced consumption of food containing antioxidants (fruits and vegetables), increased omega-6 polyunsaturated fatty acids (PUFA) intake and reduced omega-3 PUFA intake have been implicated in the increase in asthma and other allergic diseases (2). Since then, and in addition to epidemiological studies, interventional studies of several nutrients, such as probiotics, prebiotics, omega-3 PUFA and antioxidants for allergic diseases, have been performed. However, due to limited evidence, there is no consensus yet that intake of one particular nutrient is recommended for the prevention or amelioration of any allergic disease.
Figure 1. (A) Structure of four flavonoids: quercetin, rutin, isoquercitrin and enzymatically modified isoquercitrin (EMIQ)
(B) Plasma concentration of quercetin metabolites at 1.5 hours after consumption of EMIQ or quercetin at 2 mg aglycone equivalent/kg body weight. EMIQ is much more easily absorbed than quercetin.
For this study we focused on flavonoids, a large group of low molecular weight polyphenolic secondary plant metabolites, since they possess antioxidant, anti-allergic and immune-modulating properties (1, 3), and performed randomized double-blind placebo-controlled trials to test whether intake of flavonoids could suppress allergic symptoms related to Japanese cedar pollinosis (4, 5). We selected as the subject of this study enzymatically modified isoquercitrin (EMIQ), which is a quercetin glycoside consisting of isoquercitrin and its maltooligosaccharides, generated from rutin by means of enzymatic modification (Fig. 1). This modification markedly enhances the bioavailability of EMIQ (6). Figure 2 shows the results. In every study we performed, daily intake of 100 mg (study 1 and 2) or 200 mg (study 3) of EMIQ significantly suppressed allergic symptoms, in comparison with those of a placebo control group. Although there is limited evidence that flavonoids are beneficial nutrients for allergic diseases, the findings of various epidemiological studies and the preventative and ameliorative effects of several flavonoids observed in allergic animal models support this notion (3, 7). However, further clinical evaluation will be essential to verify our findings.
Figure 2. Effects of EMIQ on allergic symptoms related to Japanese cedar pollinosis
- Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y, Ohkawara T, Hagihara K, Yamadori T, Shima Y, Ogata A, Kawase I, Tanaka T. 2007. Flavonoids and related compounds as anti-allergic substances. Allergol Int 56(2):113-23.
- Devereux G, Seaton A. 2005. Diet as a risk factor for atopy and asthma. J Allergy Clin Immunol 115(6):725-9.
- Tanaka T. 2014. Flavonoids for allergic diseases: present evidence and future perspective. Curr Pharm Des 20(6):879-85.
- Kawai M, Hirano T, Arimitsu J, Higa S, Kuwahara Y, Hagihara K, Shima Y, Narazaki M, Ogata A, Koyanagi M, Kai T, Shimizu R, Moriwaki M, Suzuki Y, Ogino S, Kawase I, Tanaka T. 2009. Effect of enzymatically modified isoquercitrin, a flavonoid, on symptoms of Japanese cedar pollinosis: a randomized double-blind placebo-controlled trial. Int Arch Allergy Immunol 149(4):359-68.
- Hirano T, Kawai M, Arimitsu J, Ogawa M, Kuwahara Y, Hagihara K, Shima Y, Narazaki M, Ogata A, Koyanagi M, Kai T, Shimizu R, Moriwaki M, Suzuki Y, Ogino S, Kawase I, Tanaka T. 2009. Preventive effect of a flavonoid, enzymatically modified isoquercitrin on ocular symptoms of Japanese cedar pollinosis. Allergol Int 58(3):373-82.
- Murota K, Matsuda N, Kashino Y, Fujikura Y, Nakamura T, Kato Y, Shimizu R, Okuyama S, Tanaka H, Koda T, Sekido K, Terao J. 2010. Alpha-Oligoglucosylation of a sugar moiety enhances the bioavailability of quercetin glucosides in humans. Arch Biochem Biophys 501(1):91-7.
- Tanaka T, Takahashi R. 2013. Flavonoids and asthma. Nutrients 5(6):2128-43.